An estimated 18.2 million people (6.3 percent of the population) in the United States have diabetes;90 to 95 percent of all diagnosed cases are type II diabetes (NIDDK, 2005). The search for new and more effective therapies to address the growing number of Americans with type II diabetes and related conditions is currently hindered by the lack of a research animal model that closely resembles the human diabetic condition. All rat models currently available commercially, related to metabolic syndrome and overt type II diabetes, have a genetic defect in leptin-receptor. On the contrary, leptin and leptin-receptor defects are not common causes for the etiology of obesity and diabetes in the human population. A rat model without this defect would more closely resemble the human condition and thus be more appropriate for the study of diabetic-related conditions and metabolic syndrome. PreClinOmics (PCO) has begun to develop a new rat model without leptin/leptin-receptor defects by crossing a selected rat model with the propensity to develop diabetes with a model that has the propensity to develop obesity. The long-term goal of this project is to create a rat model that will be accepted by biotech and pharmaceutical industries, and the research community to advance the study and development of type II diabetic therapies in humans. PCO achieved and exceeded its specific aims in Phase I of this project. Phase II will focus on the continued development, defining, characterization and utility of the new diabetic rat model. This project has six specific aims: 1) Continue selective breeding and utilize genetic monitoring to achieve genetic and phenotypic homogeneity. 2) Use dietary manipulation to modify obesity, other characteristics of "metabolic syndrome" and the age of onset and synchronization of the onset of diabetes. 3) Test therapeutic compounds for the prevention and treatment of obesity and diabetes. 4) Evaluate the time of appearance and levels of known markers and endpoints of obesity, metabolic syndrome and diabetes. 5) Evaluate leptin tolerance. 6) Collaborate with University and pharmaceutical partners to generate interest, independent data and publications. A strong commercial market exists for this new rat model;drug developers including Eli Lilly &Company, Glaxo Smith Kline, and others PCO has met with have already expressed a strong interest in establishing collaborative arrangements and eventually purchase agreements. Project Narrative: Current commercially available animal models that are used for obesity and diabetes research and drug development have genetic defects that cause obesity. These defects are not found in the typical obese and diabetic individuals where polygenetic genes seem to be responsible for the condition. The purpose of this project is to develop and produce a new animal model that has polygenetic obesity (does not have a leptin or leptin receptor defect) which develops into diabetes. This should be a very important model to develop drugs that will control obesity and adult onset diabetes.